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The natural small molecules can inhibit protein aggregation and underlying cellular pathogenesis of neurodegenerative diseases involving multi\u2010factorial mechanisms of action. Certain natural small molecular inhibitors of pathogenic protein aggregation are highly efficient and have shown promising therapeutic potential. In the present study, Shikonin (SHK), a natural plant\u2010based naphthoquinone has been investigated for its aggregation inhibition activity against \u03b1\u2010synuclein (\u03b1\u2010syn) and the neuroprotective potential in\n                    <jats:italic>Caenorhabditis elegans (C. elegans)<\/jats:italic>\n                    . SHK significantly inhibited aggregation of \u03b1\u2010syn at sub\u2010stochiometric concentrations, delayed the linear lag phase and growth kinetics of seeded and unseeded \u03b1\u2010syn aggregation. The binding of SHK to the C\u2010terminus of \u03b1\u2010syn maintained \u03b1\u2010helical and disordered secondary structures with reduced beta\u2010sheet content and complexity of aggregates. Further, in\n                    <jats:italic>C. elegans<\/jats:italic>\n                    transgenic PD models, SHK significantly reduced \u03b1\u2010syn aggregation, improved locomotor activity and prevented dopaminergic (DA) neuronal degeneration, indicating the neuroprotective role of SHK. The present study highlights the potential of natural small molecules in the prevention of protein aggregation that may further be explored for their therapeutic efficacy in the management of protein aggregation and neurodegenerative diseases.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15907-fig-0006-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  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